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ReferenceGRCh38 38.1/141
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Asthma is a disorder that causes the airways of the lungs to swell and narrow, leading to wheezing, shortness of breath, coughing, and chest tightness. Asthma is caused by a complex interaction between genetic and environmental factors [PMID 18197984OA-icon.png]. The inheritance of asthma through genetics has been recognized and demonstrated in twin studies where they found monozygotic twins are more concordant for asthma and other allergic traits than dizygotic twins [PMID 10712375]. Family-based linkage studies have indicated various asthma related genes such as ADAM33, DPP10, NPSR1, PHF11 and HLA-G [PMID 12110844][PMID 14566338] [PMID ] [PMID 12754510] [PMID 15611928OA-icon.png]. However these findings have low reproducibility in the general population because variants in the family-based studies are rare high-risk alleles that are normally only found in families. Genome-wide association studies (GWAS) have also been used to find specific asthma candidate genes.

Background: Rs533116 (major: G; risk: A) is located in the CRTh2 gene. CRTh2 (chemoattractant-receptor homologous molecule expressed on Th2 cells) is expressed in Th2 cells and other cells that are involved in allergic inflammation. Previous studies have shown that single nucleotide polymorphisms in CRTh2 are associated with allergic asthma in distinct ethnic populations [PMID 15345705] [PMID 18777142] [PMID 19392992]. Rs533116 brought to the attention of researchers in a study done in 2010 in Korea [PMID 19392992]. Rs533116 showed a weak association with asthma that was mentioned but not emphasized in Palikhe et al. 2010 [PMID 19392992]. However, Campos Alberto et al. 2012 have done further research (statistically and biologically) to show that this variant is associated with asthma allergy that is specific to Europeans [PMID 22947041].

CRTh2 is a G-protein-coupled receptor for prostaglandin. CRTh2 plays an important role in allergic inflammation through the expression of Th2 cytokines and chemotaxis. Past research has shown that CRTh2 antagonists exposed to wild-type and crth2 -/- knockout mice both show allergic asthma like responses [PMID 19796209]. In humans, allergic rhinitis is resulted in the increase of CRTh2-expressing cells in the nasal mucosal. In addition, human asthmatics have increased levels of lung T cells expressing CRTh2 and increased levels of PGD2 levels after exposure to allergen. Thus there are various sources of evidence to indicate CRTh2 as a pathway involved in allergic responses [PMID 19796209].

Research: Since Rs533116 was found to have a weak association in previous studies done in Korea, Campos Alberto et al. 2012 pursued the question of whether or not Rs533116 is associated with asthma [PMID 19392992]. The study in Korea looked a three study groups – 107 patients with aspirin exacerbated respiratory disease compared to aspirin-tolerant asthma patients and 133 normal healthy controls [PMID 19392992]. Campos Alberto et al. 2012 followed up the Rs533116 variant because they reasoned that this variant may represent an independent risk factor because it was not in linkage disequilibrium with other associated asthma SNPs. Campos Alberto et al. 2012 showed that Rs533116 is associated with both allergic asthma and increase expression of CRTh2 in European adults (this study has not been replicated) [PMID 22947041].

The study done by Campos Alberto et al. 2012 looked at 1282 people for the CRTh2 Rs533116 SNP. They started with four groups: European, East Asians, South Asians, and other. Although at first four ethnic groups were looked, only the European group was analyzed because the A allele frequency was too low in the other ethnicities (South Asians (5.9%), and East Asians (%0.5)). The frequency Rs533116 (AA genotype) was analyzed in European people (14.6%). For the Europeans alone, the study had 618 people (35 with allergic asthma and 583 controls). The AA genotype in the European population showed a significant association with allergic asthma has an odds ratio (OR) of 2.67; 95% CI, 1.09-6.55 I (P-value: 0.02).

To further validate the findings, Campos Alberto et al. 2012 analyzed expression of CRTh2 by examining the frequency of eosinophils (white blood cells) in asthmatic and non-asthmatic patients before and after exposure to allergens. The frequency of eosinophils was quantified in subjects with Rs533116 genotype and in the controls. This study analyzed 4 people with each genotype (AA, GG, GA). On average after allergen exposure subjects with the AA genotype showed a 2.3-fold (P-value: 0.0173) increase in eosinophils compared to the GG genotype. However, no statistical significance was observed between GA and GG (1.5-fold P-value: 0.31).

Limitations of research:

In conclusion, Campos Alberto et al. 2012 found that the A allele is associated with having a higher risk of more severe asthma phenotypes in Europeans. On average subjects with the AA genotype show an increase percentage of circulating eosinophils than those of GG genotype when exposed to allergens. However, there are limitations in this study to keep in mind. One must take into consideration that this study first looked at different ethnic groups for the variant but in the end they threw out all groups except European. The statistical analysis has its limitations because it used a small sample size. Campos Alberto et al. 2012 also looked at CRTh2 expression through quantifying eosinophils but the sample size again was small (total of 12 people). More research needs to be done Rs533116 to determine if it is truly associated with allergic asthma.